Reinvigorating exhausted T cells in cancer and chronic viral infections cells. However, in chronic viral infection and cancer, the killer cells often lapse into “exhausted” CD8+ T cells that no longer can stem disease

BIRMINGHAM, Ala. – Killer immune cells destroy cancer cells and cells infected by virus. These CD8 ⁺ T cells are activated after detection of viral infection or growth of “non-self” tumor cells. However, in chronic viral infection and cancer, the killer cells often lapse into “exhausted” CD8 ⁺ T cells that no longer can stem disease.

This exhaustion is a major barrier in the new immunotherapies for cancer, including immune checkpoint blockers and CAR T cell therapy. In a detailed study of exhausted T cell subsets reported in Nature Communications , University of Alabama at Birmingham researchers led by Lewis Z. Shi, M.D., Ph.D., show that a transcriptional repressor called Gfi1, or growth factor independent-1, is a key regulator of the subset formation of exhausted CD8 ⁺ T cells and may offer a key to reducing exhaustion.

“Our study identifies an important role of Gfi1 in orchestrating CD8 ⁺ T cell response to anti-CTLA-4 therapy, the very first U.S. Food and Drug Administration-approved immune checkpoint blocker to treat patients with advanced cancer,” said Shi, a professor in the UAB Department of Radiation Oncology . “We reason that fine-tuning Gfi1 activity in T cells may prevent or reverse T cell exhaustion to bolster immune checkpoint blockade efficacy.”

Exhausted CD8 ⁺ T cells are a complex population of subsets composed of progenitor cells and “effector-like” or “terminally exhausted” cells. Effector-like cells still retain some killer ability. The UAB researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108 ⁺ CX ₃ CR1 ⁺ subset that expresses low levels of Gfi1, while other established subsets have high expression.

Notable key features of the Ly108 ⁺ CX ₃ CR1 ⁺ subset include: First, the Ly108 ⁺ CX ₃ CR1 ⁺ subset has a distinct chromatin profile from the other sets, meaning a changed accessibility to certain genes on the chromosome. Second, that subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. Third, this process depends on Gfi1.

To demonstrate a role for Gfi1 in immune checkpoint blockade therapy, the UAB team tested anti-CTLA-4 therapy in a mouse bladder cancer model, comparing mice that had T cells with either wild-type Gfi1 or Gfi1 knockout. They found that the anti-CTLA-4 therapy significantly inhibited tumor growth in wild-type but not Gfi1 knockout mice. Similarly, anti-CTLA-4 therapy promoted infiltration and/or expansion of CD4 ⁺ and CD8 ⁺ tumor-infiltrating lymphocytes in wild-type but not Gfi1 knockout mice. These observations were largely corroborated in a second mouse model of colorectal adenosarcoma, MC38.

“Considering Gfi1 downregulation is associated with the active differentiation of CD8 ⁺ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108 ⁺ CX ₃ CR1 ⁺ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors,” Shi said.

Along with a recent report by others of promising outcomes in small cell lung cancer from combining a lysine-specific histone demethylase inhibitor with the anti-PD-1 immune checkpoint blocker, “further testing of this combination approach should be conducted in melanoma, bladder cancer and colorectal adenocarcinoma, especially those resistant to immune checkpoint blockers,” Shi said.

Co-authors with Shi in the study , “Gfi1 controls the formation of effector-like CD8 ⁺ T cells during chronic infection and cancer,” are Oluwagbemiga A. Ojo, Hongxing Shen and James A. Bonner, UAB Department of Radiation Oncology; Jennifer T. Ingram and Allan J. Zajac, UAB Department of Microbiology ; Robert S. Welner, UAB Department of Medicine Division of Hematology and Oncology ; and Georges Lacaud, The University of Manchester, Manchester, United Kingdom.

At UAB, Radiation Oncology, Microbiology and Medicine are departments in the Marnix E. Heersink School of Medicine . Shi is a scientist in the O’Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.

Nature Communications

10.1038/s41467-025-59784-1

Experimental study

Animals

Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer

15-May-2025

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